Sulfadiazine handling in the rabbit. II. Mechanisms of nonlinear kinetics of elimination
Du Souich, P.; McLean, A.J.; Lalka, D.; Vicuna, N.; Chauhuri, E.; McNay, J.L.
Journal of Pharmacology and Experimental Therapeutics 207(1): 228-235
1978
ISSN/ISBN: 0022-3565 PMID: 702344 Document Number: 135868
Sulfadiazine (SDZ) was administered to slow and fast acetylator rabbits in doses of 20, 40 and 80 mg/kg. In paired experiments, the mean plasma half-life (t12.beta.) of SDZ increased from 60.1 min after a 20 mg/kg dose to 82.8 min after a 40 mg/kg dose (P < .001) and 81.5 min at the 80 mg/kg level, without change in renal clearance and nonrenal clearance. Apparent volume of distribution increased with dose covarying with t1/2.beta. (r = 0.52, P < .005 for fast and r = 0.62, P < 001 for slow acetylator rabbits). Since protein binding changes can alter apparent volume of distribution, the in vitro protein binding of SDZ and its metabolite N-acetylsulfadiazine (NSDZ) was studied over the in vivo concentration range. Free fraction of SDZ increased from 10.7 to 53.8% over the range 17-365 .mu.g/ml while NSDZ free fraction increased from 0.4 to 21% as NSDZ was increased from 18 to 83 .mu.g/ml. NSDZ (57-240 .mu.g/ml) significantly increased SDZ free fraction (P < .001). Coadministration of 10 mg/kg of NSDZ with 20 mg/kg of SDZ increased SDZ increased SDZ t1/2.beta. in paired experiments from 64.8 to 77.2 min (P < .02), reflecting the combined influence of change in apparent volume of distribution and a decreased renal clearance. Changes in binding of drug to tissue(s) are proposed as part explanation of these findings of nonlinear kinetics.